Therapeutic Potentials of a New Long Noncoding RNA in Diabetic Bone Wound Repair

新型长非编码 RNA 在糖尿病骨伤口修复中的治疗潜力

• 批准号: 10684848
• 负责人: JAKE JINKUN CHEN
• 金额: $ 58.9万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684848
• 关键词: Antidiabetic Drugs; Binding Proteins; Biocompatible Materials; Biological Process; Biology; Biomechanics; Blood Glucose; Bone Diseases; Bone Regeneration; Bone Resorption; Bone Tissue; Boston; Calcitonin; Cell physiology; Cellular biology; Chondrocytes; Clinic; Clinical Trials; Code; Coin; Complication; Data; Defect; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Drug Delivery Systems; Drug Targeting; Epidemic; Epigenetic Process; Experimental Pathology; Family; Foundations; Functional disorder; Future; Gene Expression; Genes; Health; Hyperglycemia; Impaired wound healing; Incidence; Knockout Mice; Laboratories; Length; Link; Lysine; Methods; Molecular; Molecular Biology; Mus; Natural regeneration; New Jersey; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; PTH gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Play; RNA; RNA Binding; Research; Research Personnel; Role; Selective Estrogen Receptor Modulators; Site; System; Techniques; Technology; Therapeutic; Therapeutic Effect; Transcript; Transcription Process; Universities; Untranslated RNA; bisphosphonate; bone; bone cell; bone fracture repair; bone healing; bone metabolism; cell type; diabetic; diabetic bone disease; efficacy evaluation; fracture risk; histone methylation; human disease; knockout gene; lipid biosynthesis; loss of function; mouse model; nanoparticle; new therapeutic target; novel; osteogenic; pharmacologic; posttranscriptional; prevent; recruit; side effect; skills; therapeutic RNA; therapeutic target; therapeutically effective; tissue repair; translational study; wound healing

Patients with type 2 diabetes (T2D) have substantially higher incidence of bone disorders, including as much as a 64% greater risk of fracture as compared to those without T2D. High blood glucose levels adversely alter bone cell functions, causing decreased bone formation and delayed wound healing with poor quality tissue repair. Therefore, diabetic bone disease (DBD) is a serious health concern for more than 40 million people in the US and 370 million in the world currently afflicted with T2D. Current treatments for DBD include anti-resorptive drugs, selective estrogen receptor modulators, and anabolic (bone-forming) drugs. However, these drugs target either the bone-formation or bone-resorption pathway, not both. Moreover, these drugs have little direct effect on diabetic hyperglycemia, a major root cause of T2D bone disorders. Furthermore, recent data indicate some anti-diabetic drugs have side effects that actually increase fracture risk in T2D. Therefore, developing a safe and effective method to prevent DBD and restore and regenerate lost bone tissue in diabetics is critically important. Long noncoding RNAs (lncRNAs) are a family of non-protein-coding transcripts with length longer than 200 nucleotides. Emerging evidence suggests that lncRNAs play important roles in gene expression and are involved the pathogenesis of many human diseases. Currently, there are over 60 clinical trials using lncRNAs as a remedy. Our laboratory has recently identified and initially characterized a specific lncRNA that promotes osteogenesis and inhibits adipogenesis in diabetes. It can recruit KDM6B and KDM4B and influence the histone methylation of relevant genes. Its deficiency causes bone abnormalities and retards bone regeneration and delays wound healing in mouse models. This newly discovered lncRNA is therefore coined “lncR-DBD”, suggesting its potential roles in targeting the pathophysiology of diabetic bone disease. We have successfully generated a lncR-DBD gene knockout mouse line which will enable us to further dissect the biological function of this new lncRNA. Aim 1 will determine the cellular localization of lncR-DBD and explore the epigenetic pathways using the state-of-the-art approaches; Aim 2 will define the mechanisms and alterations in bone phenotype in lncR-DBD knockout mice; Aim 3 will use a novel nanohydrogel delivery system to investigate the therapeutic effects of lncR-DBD on bone wound repair and fracture healing in diabetic mice. The outcome of our study will provide a paradigm shift in current understanding of the pathophysiology of DBD and have a significant impact on the future treatment of this epidemic disease. Firstly, building on our preliminary findings that lncR-DBD plays a pivotal role in bone metabolism, this project will further reveal novel epigenetic mechanisms of DBD. Secondly, we will decipher the pathways of lncR-DBD modulating genes in the diabetic microenvironment, which will lead to discovery of new therapeutic targets. Finally, we will deliver the lncR-DBD mimics using a novel nanohydrogel system as a safe, effective means for lncRNA-based therapy. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies.

2型糖尿病(T2D)患者的骨病发病率明显更高，包括AS 与那些没有T2D的人相比，骨折的风险高出%。高血糖水平对身体不利 改变骨细胞功能，导致骨形成减少，伤口愈合延迟，质量不佳 组织修复。因此，糖尿病骨疾病(DBD)是4000多万人严重关注的健康问题 目前，美国和世界上有3.7亿人患有T2D。目前治疗DBD的方法包括 抗吸收药物、选择性雌激素受体调节剂和合成代谢(骨形成)药物。然而， 这些药物只针对骨形成或骨吸收途径，而不是两者兼而有之。此外，这些药物有 对糖尿病高血糖几乎没有直接影响，糖尿病高血糖是T2D骨骼疾病的主要根本原因。此外，最近的数据 提示一些抗糖尿病药物有副作用，实际上会增加T2D的骨折风险。因此， 开发一种安全有效的方法预防DBD并恢复和再生糖尿病患者丢失的骨组织 是至关重要的。长非编码RNAs(Long Non Coding RNAs，LncRNAs)是一类长度非蛋白质编码的转录本 超过200个核苷酸。新的证据表明，lncRNAs在基因表达中起着重要作用 并与许多人类疾病的发病机制有关。目前，有60多项临床试验使用 InncRNA作为一种补救措施。我们的实验室最近发现并初步鉴定了一种特定的lncRNA 促进糖尿病患者的成骨和抑制脂肪生成。它可以招募KDM6B和KDM4B并影响 相关基因的组蛋白甲基化。它的缺乏会导致骨骼异常和骨骼发育迟缓 在小鼠模型中再生和延迟伤口愈合。这种新发现的lncRNA因此被创造出来 “LncR-DBD”，提示其在糖尿病骨疾病的病理生理学靶向中的潜在作用。我们有 成功地获得了一个lncR-DBD基因敲除小鼠系，这将使我们能够进一步剖析 这种新的lncRNA的生物学功能。目标1将确定lncR-DBD的细胞定位并探索 使用最先进的方法的表观遗传途径；目标2将定义机制和改变 在lncR-DBD基因敲除小鼠的骨表型中；Aim 3将使用一种新的纳米水凝胶递送系统来 探讨LncR-DBD对糖尿病小鼠骨创伤修复和骨折愈合的治疗作用。这个 我们的研究结果将为目前对DBD和DBD病理生理学的理解提供一个范式转变 对这种流行病的未来治疗有重大影响。首先，在我们初步的基础上 发现LncR-DBD在骨代谢中起着关键作用，该项目将进一步揭示新的表观遗传学 DBD的机理。其次，我们将破译糖尿病患者中lncR-DBD调控基因的途径。 微环境，这将导致发现新的治疗靶点。最后，我们将交付lncr-DBD 模拟使用一种新的纳米水凝胶系统作为一种安全、有效的基于lncRNA的治疗手段。一个 具有互补和协同能力的跨学科研究团队将进行研究。